Lipid reprogramming as driver of statin-targetable vulnerability in early-onset prostate cancer.

Abstract

e17147 Background: Early-onset prostate cancer (EOPC, age ≤55 years) is increasing in incidence and displays distinct clinical features. However, its biological characteristics and therapeutic targets remain insufficiently explored. Methods: We integrated Nuclear Magnetic Resonance (NMR)-based metabolomics, targeted serum proteomics, and whole-genome sequencing data from the UK Biobank with targeted-DNA and bulk RNA sequencing (RNA-seq) from West China Hospital and public repositories to comprehensively characterize metabolic reprogramming in EOPC. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed on 72 specimens from 57 patients (19 age ≤55 years, 38 age > 55 years) to delineate EOPC-specific tumor microenvironmental features. Medication records from the UK Biobank and the West China Prostate Biopsy Database (WCHPBD) were analyzed to identify actionable therapeutic targets, and drug-target Mendelian randomization was conducted for causal validation. Results: Transcriptomic and proteomic analyses consistently revealed hyperactivated lipid metabolism in EOPC, particularly enhanced cholesterol biosynthesis and adipogenesis. scRNA-seq and spatial transcriptomics localized this metabolic program to a malignant epithelial subcluster (epi-0) and SPP1⁺ tumor-associated macrophages, which were enriched and interacting in EOPC. Additionally, serum metabolomics revealed enrichment of lipid related metabolic traits in EOPC, which predicted and causally contributed to EOPC onset. Clinically, statin use was associated with a significantly reduced EOPC risk (HR = 0.30, 95% CI 0.18–0.50, P < 0.001) and improved disease-specific survival (HR = 0.53, 95% CI 0.30–0.94, P = 0.027). Mendelian randomization confirmed that genetic inhibition of HMGCR, the statin target, decreased EOPC risk across independent cohorts. Conclusions: Our findings reveal dysregulated lipid metabolism serves as a defining driver of EOPC and provide convergent molecular, epidemiological, and causal genetic evidence supporting the use of HMGCR inhibitors as an accessible and effective strategy for EOPC prevention and treatment.